1. Field of the Invention
The present invention relates to a method of control of parasites in animals, compositions comprising a compound effective for said control and new compounds effective against parasites.
2. Related Art
The state of the art is represented by Hatton et al U.S. Pat. No. 5,232,940, Stetter et al U.S. Pat. No. 5,580,843, Huang et al U.S. Pat. No. 5,556,873, EP 0511845, WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278, WO 98/28279, EP 0295117, EP 0846686, EP 0659745, WO 97/22593 and EP 0811615.
It is generally a goal of agronomists and veterinarians to possess sufficient means to control pests, particularly arthropods, when they attempt to invade or attack mammals, particularly domestic animals and/or livestock. A classical method of controlling such pests has been the use of topical and/or systemic pesticides on or in the domestic animal which is being attacked. Generally effective treatments include the oral administration of insect growth regulators, such as lufenuron, or antihelminth compounds such as an ivermectin or an avermectin, or the topical application of the insecticide fipronil. It is advantageous to apply pesticides to animals in oral form so as to prevent the possible contamination of humans or the surrounding environment.
It is an object of the present invention to provide new pesticides which may be used in domestic animals.
Another object of the invention is to provide safer pesticides for domestic animals.
Another object of the invention is to provide new pesticides for domestic animals that are may be used in lower doses than existing pesticides.
These objects are met in whole or in part by the present invention.
The present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (I): 
wherein:
R1 is cyano, acetyl, C(S)NH2, alkyl, haloalkyl, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R2 is S(O)nR3, C2-C3 alkenyl, C2-C3 haloalkenyl, cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R3 is alkyl or haloalkyl;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6, xe2x80x94Nxe2x95x90C(R5)xe2x80x94N(R7)xe2x80x94R8, or xe2x80x94N(R9)xe2x80x94C(R5)xe2x95x90NR6;
R5 is hydrogen, alkyl, or alkyl substituted by halogen, alkoxy, haloalkoxy or xe2x80x94S(O)mR15;
R6 and R7 each independently represent hydrogen, alkyl, C3-C5 alkenyl or C3-C5 alkynyl; or
alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; or
R6 and R7 may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;
R8 is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, R14COxe2x80x94 or xe2x80x94S(O)tR10;
R9, R10 and R14 are alkyl or haloalkyl;
R11 and R12 are independently selected from halogen, hydrogen, CN and NO2;
R13 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)qCF3, and xe2x80x94SF5;
R15 is alkyl or haloalkyl;
X is selected from nitrogen and Cxe2x80x94R12;
Z is O, S(O)a, or NR7;
a, m, n and q are independently selected from 0, 1, and 2; and
t is 0 or 2;
and veterinarily acceptable salts thereof.
In another aspect, the present invention provides a method of controlling parasites in or on an animal comprising administering orally to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (XX): 
wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, alkyl, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R202 is S(O)hR203, C2-C3 alkenyl, C2-C3 haloalkenyl, cycloalkyl, halocycloalkyl or C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is xe2x80x94N(R205)C(O)CR206R207R208, xe2x80x94N(R205)C(O)aryl, or xe2x80x94N(R205)C(O)OR207;
R205 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl, alkoxyalkyl, haloalkoxyalkyl, C3-C5 alkenyl, C3-C5 haloalkenyl, C3-C5 alkynyl, C3-C5 haloalkynyl;
R206 is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, formyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, haloalkylamino, di(haloalkyl)amino, cycloalkyloxy, halocycloalkyloxy, alkoxyalkoxy, haloalkoxyalkoxy, alkoxyalkoxyalkoxy, aryloxy, or arylalkoxy;
R207 and R208 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; or R207 and R208 may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X1 is selected from nitrogen and Cxe2x80x94R212;
R211 and R212 are independently selected from halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)kCF3, and xe2x80x94SF5; and
h and k are independently selected from 0, 1, and 2;
and veterinarily acceptable salts thereof.
By the term xe2x80x9cveterinarily acceptable saltsxe2x80x9d is meant salts the anions of which are known and accepted in the art for the formation of salts for veterinary use. Suitable acid addition salts, e.g. formed by compounds of formulae (I) and (XX) containing a basic nitrogen atom, e.g. an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids for example acetic acid.
Unless otherwise specified, alkyl and alkoxy groups here and throughout this specification are generally lower alkyl and alkoxy groups, that is having from one to six carbon atoms, preferably from one to four carbon atoms. Generally, the haloalkyl, haloalkoxy and alkylamino groups have from one to four carbon atoms. The haloalkyl and haloalkoxy groups can bear one or more halogen atoms; preferred groups of this type include xe2x80x94CF3 and xe2x80x94OCF3. Cycloalkyl groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms and may be substituted by one or more halogen atoms. Alkenyl, haloalkenyl, alkynyl, and haloalkynyl groups generally contain from 3 to 5 carbon atoms. By the term aryl is generally meant phenyl, pyridyl, furyl, and thiopheneyl (thienyl), each of which is optionally substituted by one or more halogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, hydroxy, amino, alkylamino or dialkylamino. In compounds of formula (I), by the term substituted alkyl is meant alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R15 is alkyl or haloalkyl and m is zero, one or two. Preferably in compounds of formula (I), alkyl groups are generally substituted by from one to five halogen atoms, preferably from one to three halogen atoms. Chlorine and fluorine atoms are preferred.
The above definitions of alkyl, alkoxy and various other groups of course pertain not only to those radicals themselves but also to those portions of larger radicals.
Compounds of formula (I) wherein R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6, Z is NR7 and R6 represents a hydrogen atom may exist as the tautomeric double bond isomer form xe2x80x94NHxe2x80x94C(R5)xe2x95x90Nxe2x80x94R7. It is to be understood that both such forms are embraced by the present invention.
In compounds of formula (XX) the following examples of radicals are provided:
an example of cycloalkylalkyl is cyclopropylmethyl;
an example of cycloalkoxy is cyclopropyloxy;
an example of alkoxyalkyl is CH3OCH2xe2x80x94;
an example of alkoxyalkoxy is CH3OCH2Oxe2x80x94;
an example of alkoxyalkoxyalkoxy is CH3OCH2OCH2Oxe2x80x94;
an example of aryloxy is the phenoxy radical; and
an example of the arylalkoxy radical is benzyloxy or 2-phenylethoxy.
Generally, in dialkylamino or di(haloalkyl)amino radicals, the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another.
It is also to be understood that enantiomeric and diastereomeric forms of the compounds of formulae (I) and (XX) and salts thereof are embraced by the present invention. Compounds of formula (I) may be generally prepared according to known processes, for example as described in European Patent Publication 0511845 or other processes according to the knowledge of a man skilled in the art of chemical synthesis.
By the term xe2x80x9cnon-emeticxe2x80x9d is meant a compound or composition that does not generally elicit emesis from the animal when a protective, preventative or cleaning dose is administered to the animal. By the term xe2x80x9cemesisxe2x80x9d is meant vomiting. Generally an emetic substance elicits emesis in less than 24 hours after administration, usually less than 8 hours, more usually less than 2 hours. By the term xe2x80x9csubstantially non-emeticxe2x80x9d is meant that, generally, when a compound or composition of the invention is administered to a population of animals, more than 70% (or at least ⅔) of the animals are free of emesis. Preferably, more than 80%, most preferably more than 90%, of said population is free of emesis.
A preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:
R1 is cyano or alkyl;
R2 is S(O)nR3;
R3 is alkyl or haloalkyl;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6;
R5 is hydrogen, alkyl or haloalkyl;
Z is O, S(O)a, or NR7;
R6 and R7 are independently selected from hydrogen and unsubstituted or substituted alkyl; or
R6 and R7 may form together with the nitrogen to which they are attached a 3 to 7 membered ring which may additionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur;
X is selected from nitrogen and Cxe2x80x94R12;
R11 and R12 are independently selected from halogen, hydrogen, CN and NO2;
R13 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)qCF3, and xe2x80x94SF5;
a, n and q are independently selected from 0, 1, and 2.
Preferably R6 is alkyl which is substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, sulfide, sulfoxide, sulfone, or phenyl or pyridyl moieties of which each phenyl or pyridyl moiety is optionally substituted with one or more groups selected from halo, nitro, and alkyl.
Preferably the method of the invention has one or more of the following features:
R1 is cyano;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6 and Z is xe2x80x94NR7;
X is Cxe2x80x94R12; R11 and R12 represent a chlorine atom; and R13 is CF3, OCF3 or xe2x80x94SF5;
R12 is xe2x80x94S(O)nCF3 and n is 0, 1, or 2.
A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:
R1 is cyano or alkyl; R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6; and R5 is hydrogen or C1-C3 alkyl.
The compounds of formula (I) for use in the control of parasites in animals preferably have one or more of the following features:
R1 is cyano or methyl;
R3 is halomethyl (preferably CF3);
R11 and R12 each independently represent a halogen atom;
X is Cxe2x80x94R12;
R13 is haloalkyl (preferably CF3), haloalkoxy (preferably OCF3), or xe2x80x94SF5; or
n is 0, 1 or 2 (preferably 0 or 1).
A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:
R1 is cyano;
R2 is S(O)nR3;
R3 is halomethyl;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6;
Z is NR7;
R5 is hydrogen or alkyl;
R6 and R7 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;
X is selected from nitrogen and C-R12;
R11 and R12 each independently represent a halogen atom;
R13 is selected from haloalkyl, haloalkoxy and xe2x80x94SF5;
R15 is alkyl or haloalkyl; and
m and n are independently selected from 0, 1, and 2.
A further preferred class of compounds of formula (I) for use in the control of parasites in animals is that wherein:
R1 is cyano;
R2 is S(O)nCF3;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6 or xe2x80x94Nxe2x95x90C(R5)xe2x80x94N(R7)xe2x80x94R8;
Z is NR7;
R5 is hydrogen or alkyl;
R6 and R7 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;
R8 is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)tR10;
X is selected from nitrogen and Cxe2x80x94R12;
R10 and R15 independently represent alkyl or haloalkyl;
R11 and R12 each represent a chlorine atom;
R13 is CF3 or xe2x80x94SF5; and
m and n are 0, 1 or 2; and t is 0 or 2.
A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:
R1 is cyano;
R2 is S(O)nCF3;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6;
Z is NR7;
R5 is hydrogen or methyl;
R6 and R7 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl;
X is Cxe2x80x94R12;
R11 and R12 each represent a chlorine atom;
R13 is CF3 or xe2x80x94SF5;
R15 is alkyl or haloalkyl;
m is zero, one or two; and
n is 0 or 1.
A further preferred class of compounds of formula (I) for use in the control of parasites in animals are those wherein:
R1 is cyano;
R2 is S(O)nCF3;
R4 is xe2x80x94Nxe2x95x90C(R5)xe2x80x94Zxe2x80x94R6;
Z is NR7;
R5 and R7 each represent a hydrogen atom;
R6 is alkyl or haloalkyl;
X is Cxe2x80x94R12;
R11 and R12 each represent a chlorine atom;
R13 is CF3 or xe2x80x94SF5; and
n is 0.
Compounds of formula (XX) which are preferred according to the present invention are those wherein:
R201 is cyano;
R202 is S(O)hR203;
R203 is alkyl or haloalkyl;
R204 is xe2x80x94N(R205)C(O)CR206R207R208;
R205 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl and halocycloalkylalkyl;
R206 is alkoxy, haloalkoxy, or hydrogen;
R207 and R208 are independently hydrogen, alkyl, or haloalkyl; or
R207 and R208 may form together with the carbon to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X1 is selected from nitrogen and Cxe2x80x94R212;
R211 and R212 are independently selected from halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)kCF3, and xe2x80x94SF5; and
h and k are independently selected from 0, 1, and 2.
A preferred group of compounds of formula (XX) is that wherein the ring which is formed by R207 and R208 is interrupted by one or more heteroatoms, more preferably one oxygen atom.
The compounds of formula (XX) of the present invention preferably have one or more of the following features:
R201 is cyano;
R203 is halomethyl, preferably CF3;
R211 and R212 are independently halogen;
X1 is Cxe2x80x94R212;
R213 is haloalkyl, haloalkoxy or xe2x80x94SF5; or
h is 0 or 1, or 2, preferably 0 or 1.
A preferred class of compounds is that wherein R204 is N(R205)C(O)CR206R207R208.
Another preferred class of compounds is that wherein R204 is N(R205)C(O)aryl.
Another preferred class of compounds is that wherein R204 is N(R205)C(O)OR207.
Preferably R205 is C1-C4 alkyl, more preferably C1-C2 alkyl, most preferably methyl.
Preferably R206 is alkoxy, most preferably methoxy, ethoxy or propoxy.
Preferably R207 and R208 are both hydrogen.
Among the compounds which may be used in the invention some are new and hence in another aspect of the present invention there is provided a compound of formula (II): 
wherein:
R21 is cyano, alkyl, haloalkyl, acetyl, xe2x80x94C(xe2x95x90S)NH2, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R22 is S(O)mR23;
R23 is alkyl or haloalkyl;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27) or xe2x80x94Nxe2x95x90C(R25)xe2x80x94N(R27)xe2x80x94R28;
R25 represents hydrogen or alkyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy or xe2x80x94S(O)mR35;
R26 and R27 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR35; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R35 is alkyl or haloalkyl and m is zero, one or two;
X is selected from nitrogen and Cxe2x80x94R32;
R28 is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)tR30;
R30 is alkyl or haloalkyl;
R31 and R32 are independently selected from halogen, hydrogen, CN and NO2;
R33 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)rCF3, and xe2x80x94SF5;
m and r are independently selected from 0, 1, and 2; and t is 0 or 2; with the exclusion of the compound wherein R21 is cyano; R22 is xe2x80x94SCF2CH3; R25 is hydrogen; X is Cxe2x80x94R32; R26 and R27 are methyl; R31 and R32 are chlorine; and R33 is trifluoromethyl; and veterinarily acceptable salts thereof.
A further class of novel compounds of formula (II) are those wherein:
R21 is cyano or methyl;
R22 is S(O)mR23;
R23 is haloalkyl;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27);
R25 and R27 are hydrogen or unsubstituted or substituted alkyl;
R26 is haloalkyl;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 are independently selected from halogen, hydrogen, CN and NO2;
R33 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)rCF3, and xe2x80x94SF5;
m and r are independently selected from 0, 1, and 2; with the exclusion of the compound wherein R21 is cyano; R22 is xe2x80x94SCF2CH3; R25 is hydrogen; X is Cxe2x80x94R32; R26 and R27 are methyl; R31 and R32 are chlorine; and R33 is trifluoromethyl.
A preferred class of novel compounds of formula (II) are those wherein:
R21 is cyano;
R22 is S(O)mR23;
R23 is halomethyl;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27);
R25 is hydrogen or alkyl;
R26 and R27 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R15 is alkyl or haloalkyl and m is zero, one or two;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 each represent a chlorine atom;
R33 is selected from haloalkyl, haloalkoxy and xe2x80x94SF5;
m is selected from 0, 1, and 2.
A further preferred class of novel compounds of formula (II) are those wherein:
R21 is cyano;
R22 is S(O)mCF3;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27); or xe2x80x94Nxe2x95x90C(R25)xe2x80x94N(R27)xe2x80x94R28;
R25 is hydrogen or methyl;
R26 and R27 each independently represent hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R15 is alkyl or haloalkyl and m is zero, one or two;
R28 is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino or xe2x80x94S(O)tR30;
X is selected from nitrogen and Cxe2x80x94R32;
R30 is alkyl or haloalkyl;
R31 and R32 each represent a chlorine atom;
R33 is CF3 or xe2x80x94SF5; and
m is 0, 1 or 2; and t is 0 or 2.
A more preferred class of novel compounds of formula (II) are those wherein:
R21 is cyano;
R22 is S(O)mCF3;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27);
R25 and R27 each independently represent hydrogen or methyl;
R26 represents hydrogen, alkyl, alkenyl or alkynyl; or alkyl substituted by one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or xe2x80x94S(O)mR15; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R15 is alkyl or haloalkyl and m is zero, one or two;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 each represent a chlorine atom;
R33 is CF3 or xe2x80x94SF5; and
m is 0, 1 or 2.
An especially preferred class of novel compounds of formula (II) are those wherein:
R21 is cyano;
R22 is S(O)mCF3;
R24 is xe2x80x94Nxe2x95x90C(R25)N(R26)(R27);
R25 and R27 each represent a hydrogen atom;
R26 is alkyl or (preferably) haloalkyl;
X is Cxe2x80x94R32;
R31 and R32 each represent a chlorine atom;
R33 is CF3 or xe2x80x94SF5; and
m is 0.
In another aspect of the present invention there is provided a compound of formula (XX) or a salt thereof as hereinbefore defined, provided that the compound is not 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(N-ethoxycarbonyl-N-methyl)amino-4-trifluoromethylthiopyrazole.
Most preferably, the following compounds of formulae (I) and (XX) are preferred according to the present invention as listed in Tables 1 to 13. The Compound Numbers are for identification purposes only. The following symbols are hereby defined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; n-Bu means n-Butyl, and n-Pent means n-Pentyl; Cy means cyclopropyl.
The following compounds of formula (XX) are preferred according to the present invention as listed in Tables 4-12.
The present invention also relates to a composition comprising a parasiticidally effective, substantially non-emetic amount of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof and an acceptable carrier. Acceptable carriers for the use of the compounds are generally known to the skilled addressee concerned with arthropod pest control in animals, particularly domestic animals, most preferably dogs or cats.
The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof. The remainder of the composition up to 100% comprises a carrier as well as generally various additives. In this specification and the accompanying claims, percentages are by weight.
The diluted liquid formulations generally comprise from about 0.001 to about 3% of compound of formula (I) or a salt thereof or compound of formula (XX) or a salt thereof, preferably from about 0.1 to about 0.5% .
Solid formulations generally comprise from about 0.1 to about 8% of compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, preferably from about 0.5 to about 1.5%.
Compositions for oral administration comprise one or more of the compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof in association with veterinarily acceptable carriers or coatings and include, for example, tablets, pills, capsules, gels, drenches, medicated feeds, medicated drinking water, medicated dietary supplements, slow-release boluses or other slow-release devices intended to be retained within the gastrointestinal tract. Any of these may incorporate the active ingredients contained within micro-capsules or coated with acid-labile or alkali-labile or other pharmaceutically acceptable enteric coatings. Feed premixes or concentrates containing compounds of the present invention for use in preparation of medicated diets, drinking water or other materials for consumption by animals may also be used. In a highly preferred embodiment, the compositions are administered postprandially, preferably from just after a meal to 2 hours after the meal.
In a highly preferred embodiment, there is provided a product which is readily chewed by the animal and which product does generally not allow human contamination when the product is provided to the animal by hand.
The compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof may be administered before, during or after meals. The compounds of general formula (I) or salts thereof or compounds of formula (XX) or salts thereof may be mixed with a carrier and/or a foodstuff.
According to the present invention the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof formula (I) is administered orally in a dose to the animal in a dose range generally from 0.1 to 500 mg/kg of the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof (I) per kilogram of animal body weight (mg/kg), preferably from 1 to 100 mg/kg, more preferably from 1 to 50 mg/kg, even more preferably from 2 to 25 mg/kg, most preferably from 3 to 15 mg/kg.
According to the present invention, the frequency of treatment of the animal, preferably the domestic animal to be treated by the compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof, is generally from about once per week to about once per year, preferably from about once every two weeks to about once every six months, more preferably from about once every two weeks to once every three months, even more preferably from about once every two weeks to about once every six weeks, and most preferably from about once every three weeks to about once every five weeks. Most highly desirable treatment is about once a month.
Generally the animal to be treated is a domestic animal, preferably a domestic companion animal. More preferably the animal to be treated is a dog and/or a cat.
The compounds of the invention may be administered most advantageously with another parasiticidally effective material, such as an endoparasiticide, and/or an ectoparasiticide, and/or an endectoparasiticide. For example, such compounds include, namely macrocyclic lactones such as avermectins or milbemycins e.g., ivermectin; pyratel (generally administered as pyrantel pamoate) or an insect growth regulator such as lufenuron or methoprene.
By the term xe2x80x9cparasitesxe2x80x9d as used in the specification and claims is meant endoparasites and ectoparasites of warm-blooded animals, particularly ectoparasites. Preferably, fleas and/or ticks are controlled by the method of the present invention.
Illustrative of specific parasites of various host animals which may be controlled by the method of this invention include arthropods such as:
Mites: Mesostigmata spp. e.g. mesostigmatids such as the chicken mite, Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp. for example Sarcoptes scabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g. Trombiculidae spp. for example the north american chigger, Trombicula alfreddugesi; 
Ticks: e.g., soft-bodied ticks including Argasidae spp. for example Argas spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example Rhipicephalus sanguineus, and Boophilus spp.;
Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;
Fleas: e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans);
True bugs: e.g., Cimicidae or including the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.;
Bloodsucking adult flies: (e.g., horn fly [Haematobia irritans], horse fly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly [Simulium spp.], deer fly [Chrysops spp.], louse fly [Melophagus ovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anopheles spp., and Aedes spp.]); and
Parasitic fly maggots: (e.g., bot fly [Oestrus ovis and Cuterebra spp.], blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax], cattle grub [Hypoderma spp.], fleeceworm).
The present invention also relates to a use of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof hereinbefore described as a therapeutic agent, preferably for animals, more preferably for domestic animals.
The veterinary composition may be sterile or non-sterile. It may be a liquid (e.g., aqueous) or solid (e.g., dry) composition, in particular a freeze-dried composition, from which, by addition of water or another liquid, orally effective solutions may be prepared.
The present invention also relates to a use of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined for the manufacture of a veterinary composition for the control of parasites in or on an animal.
The present invention also relates to a method of cleaning animals in good health comprising the application to the animal of a compound of formula (I) or a salt thereof or a compound of formula (XX) or a salt thereof as hereinbefore defined to the animal.
The method of cleaning an animal is not a method of treatment by therapy of the animal body per se, because
(a) the animal is in good health and requires no substantial treatment to correct a deficiency of health;
(b) the cleaning of the animal is not intended to be done by veterinary personnel, but by persons interested in the cleaning of the animal; and
(c) the purpose of such cleaning is to avoid unpleasant conditions for humans and the environment which humans inhabit so as to not infest the said humans with arthropods carried by the animal.
By xe2x80x9ccarrierxe2x80x9d is meant an organic or inorganic material, which can be natural or synthetic, and which is associated with the compound and which facilitates its application to the animal. This carrier is thus generally inert and should be arthropocidally acceptable. The carrier can be solid (e.g., clay, silicates, silica, resins, wax) or liquid (e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents). An example of an oil solvent is corn oil. An example of a polar aprotic solvent is dimethyl sulfoxide.
The compounds of formula (II) wherein R21, R22, R24, R31, R33 and X are as defined above may be prepared from the compounds of formula (III): 
wherein R21, R22, R31, R33 and X are as defined above, using processes described in European Patent Publications 0511845 or 0659745, incorporated by reference herein and relied upon.
According to a feature of the present invention, compounds of formula (II) wherein R21, R22, R31, R33 and X are as defined above and R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR26R27 wherein R25, R26 and R27 are as defined above may be prepared by reacting a compound of formula (III) with a compound of formula (IV): 
wherein R25, R26 and R27 are as defined above and R100 is generally an alkyl group. The reaction is optionally conducted in the presence of a catalyst such as a mineral or organic acid (for example hydrochloric acid), generally using from 1 to 100 equivalents of (IV), preferably using 1 to 10 equivalents of (IV), and is preferably conducted in an organic solvent such as tetrahydrofuran, toluene, or N,N-dimethylformamide, at a temperature of from 0xc2x0 C. to 150xc2x0 C. Additional adjuvants such as drying agents (e.g., magnesium sulfate, potassium carbonate, or molecular sieves) may also be advantageous to the reaction. Compounds of formula (IV) are known or may be prepared by known procedures.
According to a feature of the present invention, compounds of formula (II) wherein R21, R22, R31, R33 and X are as defined above and R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR26R27 wherein R25, R26 and R27 are as defined above, may be prepared by the reaction of a compound of formula (V): 
wherein R21, R22, R25, R31, R33, X and R100 are as defined above, with a compound of formula (VI): 
wherein R26 and R27 are as defined above. The reaction is generally conducted using the same conditions as used for the preparation of compounds of formula (II) by the reaction of compounds of formula (III) with compounds of formula (IV).
According to a feature of the present invention, compounds of formula (II) wherein R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR27R28, and R21, R22, R25, R27, R31, R33 and X are as defined above, and R28 is COR34 wherein R34 is as defined above, may be prepared by the reaction of the corresponding compounds of formula (II) wherein R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR27H with an acid chloride of formula (VII):
xe2x80x83R34COClxe2x80x83xe2x80x83(VII)
wherein R34 is as defined above. The reaction is generally performed in the presence of a base such as a trialkylamine, for example triethylamine, in a solvent such as dichloromethane, at a temperature of from 0xc2x0 C. to 50xc2x0 C.
According to a feature of the present invention, compounds of formula (II) wherein R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR27R28, and R21, R22, R25, R27, R31, R33 and X are as defined above and R28 is xe2x80x94S(O)tR30 may be prepared by the reaction of the corresponding compound of formula (II) wherein R24 is xe2x80x94Nxe2x95x90C(R25)xe2x80x94NR27H with a sulfonyl chloride or a sulfenyl chloride of formula (VIII):
R30S(O)tClxe2x80x83xe2x80x83(VIII)
The reaction is generally performed in the presence of a weak base such as a trialkylamine for example triethylamine, or pyridine in a solvent such as dichloromethane, at a temperature of from 0xc2x0 C. to 50xc2x0 C.
Compounds of formulae (VI), (VII) and (VIII) are known or may be prepared by known procedures.
Compounds of formulae (III) and (V) may be generally prepared according to known processes, for example as described in International Patent Publications WO 87/03781, WO 93/06089, and WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0846686, and U.S. Pat. No. 5,232,940.
In another aspect of the present invention, compounds of formula (XX) wherein R204 is xe2x80x94N(R205)C(O)CR206R207R208, N(R205)C(O)aryl, or N(R205)C(O)OR207 are generally prepared from compounds of formula (XXI): 
by reaction with halides of formulae X2C(O)CR206R207R208, X2C(O)aryl, or X2C(O)OR207, respectively, wherein R201, R202, R205, R206, R207, R208, R211, R213, and X1 are defined above and wherein X2 is a halogen atom. The reaction is generally carried out in the presence of a base, generally using from 1 to 10 molar equivalents of the halide, and is preferably conducted in the presence of an organic solvent such as tetrahydrofuran, methylene chloride, at a temperature of from 0xc2x0 C. to 150xc2x0 C.
Compounds of formula (XXI) may be prepared from a compound of formula (XXII): 
by reaction with a compound of formula (XXIII):
X2R205xe2x80x83xe2x80x83(XXIII)
wherein R201, R202, R205, R211, R213, X1 and X2 are defined above. Compounds of formula (XXIII) are generally known in the art as alkylhalides or substituted alkythalides. Compounds of formula (XXII) may be prepared by methods described in International Patent Publications WO 87/03781, WO 93/06089, WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Publications 0295117, 0659745, 0846686, and U.S. Pat. No. 5,232,940, or other methods known to the person skilled in the art.
Alternatively compounds of formula (XXI) may be prepared by reduction of compounds of formula (XXIV): 
wherein R201, R202, R211, R213 and X1 are defined above. The reduction generally is effected by the use of a standard hydride ion donor, for example sodium borohydride or sodium cyanoborohydride. The reaction is generally effected in an polar solvent such as ethanol or methanol and generally using from 1 to 10 molar equivalents of the hydride, and is preferably conducted at a temperature of from xe2x88x92100xc2x0 C. to 150xc2x0 C.
Compounds of formula (XXIV) may be prepared using methods described in EP 0295117, WO 97/22593 or other methods known to those skilled in the art.